1
3a (100 mmol, 26.3 g) in THF (900 mL). After completion of
Then anti-15a was obtained as a colourless oil (23.54 g, 31%,
◦
the addition, the mixture was allowed to warm to −10 C and
acrolein (100 mmol, 7.3 mL) was added dropwise as a solution
in THF (100 mL). After completion of the addition, the mixture
100% by GC). R
m
f
(15% ethyl acetate in light petroleum) 0.17;
max(film)/cm 3397s br (O–H), 3078m (=C–H), 2977s (C–
H), 2936m (C–H), 2880m (C–H), 1745s (C=O), 1703s (C=O),
(250 MHz, CDCl ) 5.93–5.66
−
1
◦
was allowed to warm to 0 C and stirred at this temperature
1651m (C=C), 1640m (C=C); d
H
3
for 1 hour. The reaction mixture was quenched with ammonium
chloride (500 mL of a saturated aqueous solution). The aqueous
phase was separated and further extracted with diethyl ether
(2H, m, H-2 and H-9), 5.39 (1H, d, Jtrans 17.0, H-1a), 5.26 (1H,
2
dd, Jcis 10.6, J 1.4, H-1b), 5.08–4.94 (3H, m, H-10a, H-10b
and H-6), 4.54–4.37 (2H, m, H-3 and –OH), 3.30–3.12 (4H, m,
2
(
3 × 500 mL). The combined organic extracts were washed with
–N(CH
2
CH
3
)
2
), 2.16 (1H, dd, J 13.6, J 7.9, H-8a), 2.03 (1H,
2
brine (500 mL), dried (MgSO ), filtered and concentrated under
4
dd, J 13.6, J 7.1, H-8b), 1.14 (3H, t, J 7.1, –N(CH
1.05–0.95 (9H, m, –N(CH CH ); d (63 MHz,
and 2 × –CH
) 199.6 (dd, JC–F 33.6, 23.9), 155.6, 133.7, 132.1 (dd, JC–F
2
CH
3 2
) ),
reduced pressure to afford a pale yellow oil. Purification by
column chromatography (20% ethyl acetate in light petroleum)
afforded an inseparable diastereoisomeric mixture (1 : 2) of the
desired aldol products syn-14b and anti-14a as a pale yellow oil
2
3
)
2
3
C
2
3
CDCl
4.6, 1.5), 119.1, 118.8, 116.0 (t, JC–F 260.2), 80.0, 74.1 (t, JC–F
28.0), 44.4, 42.8, 42.3, 38.7, 23.5, 23.3, 14.4, 13.6; d (235 MHz,
3
1
2
F
2
3
(
18.8 g, 58%, 97% by GC-MS); R
f
(20% ethyl acetate in light
CDCl
3
) −113.6 (1F, dd, JF–F 261.4, JF–H 11.9), −115.5 (1F,
−
1
2
+
petroleum) 0.28; mmax(film)/cm 3399s br (O–H), 3078w (=C–
d, JF–F 261.4); [HRMS (TOF ES ) found: 370.1798. Calc. for
+
H), 2978s (C–H), 2937s (C–H), 2878s (C–H), 1744s (C=O),
C
17
H
27NO
F
Na: 370.1806; m/z (ES) 348 (100%, [M + H] ).
4
2
1
682s (C=O), 1640m (C=C); d
H
(250 MHz, CDCl ) syn/anti-
3
mixture: 5.98–5.66 (2H, m, H-2 and H-9), 5.56–5.29 (3H, m, H-
1
4
1
a, H-1b and H-10b), 5.04–4.97 (3H, m, H-10a, H-6 and –OH),
.50–4.32 (1H, m, H-3), 3.32–3.15 (4H, m, –N(CH CH ), 2.24–
.68 (4H, m, H-7 and H-8), 1.17–1.02 (6H, m, –N(CH CH );
) syn/anti-mixture: 200.0 (dd, JC–F 34.1,
Preparation of 4-(N,N-diethylcarbamoyloxy)-2,2-difluoro-
-oxo-cyclooct-7-en-1-ols cis-16a and trans-16b
2
3 2
)
2
3
3 2
)
2
d
C
(65 MHz, CDCl
3
A solution of a diastereoisomeric mixture (2 : 1) of dienes anti-
14a and syn-14b (15.0 mmol, 4.79 g) and titanium(IV) isopropox-
ide (4.50 mmol, 1.16 mL) in DCM (1.5 L) was refluxed for 30
minutes. Catalyst 2 (150 lmol, 127 mg) was added as a solution
in DCM (5 mL) and the reaction mixture was refluxed for 2 days.
Another portion of catalyst 2 (150 lmol, 127 mg) was added as a
solution in DCM (5 mL) and the reaction mixture was stirred for
an additional day. The mixture was concentrated under reduced
pressure to leave a crude diastereoisomeric mixture (1 : 2) as
a brown oil (4.53 g). Purification by column chromatography
(40% ethyl acetate in light petroleum) allowed the separation
of the two diastereoisomers. Major diastereoisomer (trans-16b)
2
2
1.9), 198.2 (dd, JC–F 30.5, 24.9), 155.8, 155.7, 136.8, 136.7,
3
3
1
31.3 (t, JC–F 3.1), 130.6 (d, JC–F 2.5), 120.5, 120.0, 116.9 (dd,
1
1
J
C–F 261.1, 256.6), 116.6, 116.5, 116.4 (dd, JC–F 261.4, 259.4),
2 2
7
4
6.9, 75.9, 73.4 (t, JC–F 27.2), 71.8 (dd, JC–F 29.0, 23.4), 42.7,
4
4
2.2, 29.9, 29.4 (d, JC–F 1.5), 29.2 (d, JC–F 2.5), 14.2, 14.1, 13.6;
(235 MHz, CDCl
d
F
3
) major diastereoisomer (anti-14a): −109.8
2 3
2
(
1F, d, JF–F 256.7), −133.9 (1F, dd, JF–F 256.7, JF–H 22.5), minor
3
diastereoisomer (syn-14b): −117.6 (d, JF–H 9.3); [HRMS (FAB,
+
[
M + H] ) found: 320.16737. Calc. for C15
H
24NO
4
2
F : 320.16734;
+
m/z (FAB) 320 (100%, [M + H] ).
was obtained as a white solid (1.88 g, 43%). R
acetate in light petroleum) 0.30; mp 93–94 C; (found C, 53.17;
f
(40% ethyl
Preparation of 6-(N,N-diethylcarbamoyloxy)-4,4-difluoro-3-
hydroxy-7,7-dimethyldeca-1,9-dien-5-ones anti-15a and syn-15b
◦
H, 7.39; N, 4.79; C13
H
21
F
2
NO
4.78%); mmax(KBr)/cm 3393s br (O–H), 2978m (C–H), 1741s
(400 MHz, CDCl , 323 K) 5.94–5.86
4
requires: C, 53.23; H, 7.22; N,
−
1
As for 14a, but from n-BuLi (120 mmol, 75 mL of a 1.6 N
solution in hexanes), 13b (29.1 g, 100 mmol) in THF (1 L) and
acrolein (132 mmol, 8.8 mL) in THF (100 mL). After completion
(C=O), 1686s (C=O); d
H
3
(1H, m, H-8), 5.57–5.52 (1H, m, H-7), 5.41 (1H, dt, J 7.0,
◦
4
of the addition, the mixture was allowed to warm to 0 C and
3.4, J 3.4, H-4), 5.09–4.98 (1H, m, H-1), 3.38–3.29 (5H, m,
stirred at this temperature for 1 hour. The reaction mixture
was quenched with ammonium chloride (1 L of a saturated
aqueous solution). The aqueous phase was separated and further
extracted with diethyl ether (3 × 750 mL). The combined organic
–OH and –N(CH
2
CH
3
)
2
), 2.41–1.99 (4H, env., H-5 and H-6),
CH ); d (63 MHz, CDCl ) 198.5
1.20–1.12 (6H, m, –N(CH
2
3
)
2
C
3
2
3
1
(t, JC–F 24.6), 154.6, 132.9, 129.5 (d, JC–F 5.1), 117.9 (t, JC–F
2
260.9), 75.5, 68.4 (t, JC–F 22.1), 42.6, 41.9, 32.4, 22.7, 14.3,
extracts were washed with brine (500 mL), dried (MgSO
4
),
13.6; d
F
(376 MHz, CDCl
3
, 223 K) major conformer: −107.6
2
2
3
filtered and concentrated under reduced pressure to afford a pale
yellow oil, which was combined with the crude product from a
second batch on the same scale to afford a total of 100.6 g of
a 1 : 1 diastereoisomeric mixture of aldol products syn-15b and
anti-15a as a pale yellow oil. Purification by (Biotage) column
chromatography (1 to 5% ethyl acetate in light petroleum)
allowed the separation of the diastereoisomers. Syn-15b was
(1F, d, JF–F 246.1), −131.5 (1F, dd, JF–F 246.1, JF–H 21.8),
2
minor conformer: −114.8 (1F, d, JF–F 231.7), −128.0 (1F, br
2
+
d, JF–F 231.7); [HRMS (FAB, [M + H] ) found: 292.13608.
Calc. for C13
H
20NO
4
F
2
: 292.13604], m/z (ES) 292 (100%, [M +
+
H] ). An analytical samplewas recrystallised byvapour diffusion
to afford colourless cubes, which were used to obtain an X-
ray crystal structure of cyclooctenol trans-16b. The minor
diastereoisomer (cis-16a) was obtained as a pale yellow solid
obtained as a colourless oil (25.06 g, 33%, 98% by GC); R
f
(15%
ethyl acetate in light petroleum) 0.23; mmax(film)/cm 3407s br
O–H), 3078m (=C–H), 2979s (C–H), 2935s (C–H), 2978s (C–
H), 1740s (C=O), 1684s (C=O), 1650m (C=C), 1640m (C=C);
(250 MHz, CDCl ) 5.96–5.66 (2H, m, H-2 and H-9), 5.52
−
1
(0.87 g, 20%). R
mp 51–52 C; (found C, 53.37; H, 7.20; N, 4.65; C13
f
(40% ethyl acetate in light petroleum) 0.24;
NO
◦
(
H
21
F
2
4
−
1
requires: C, 53.23; H, 7.22; N, 4.78%); mmax(KBr)/cm 3393s br
(O–H), 2977m (C–H), 1741s (C=O), 1687s (C=O); d
(400 MHz,
CDCl , 323 K) 5.93–5.86 (1H, m, H-8), 5.70–5.55 (1H, m, H-
7), 5.33–5.30 (1H, m, H-4), 5.07–4.99 (1H, m, H-1), 3.35–3.29
(5H, m, –N(CH CH and –OH), 2.47–1.85 (4H, H-5 and H-
6), 1.17–1.13 (6H, m, –N(CH CH ); d (63 MHz, CDCl ) 196.0
(dd, JC–F 27.2, 23.9), 153.4, 132.2, 127.1 (d, JC–F 5.6), 115.5 (t,
d
H
3
2
H
4
2
(
1H, ddd, Jtrans 17.2, J 1.4, J 1.6, H-1a), 5.36 (dt, Jcis 10.6, J
3
4
1
–
–
.4, J 1.4, H-1b), 5.08–4.94 (4H, m, H-10a, H-10b, H-6 and
OH), 4.51 (1H, dd, JF–H 22.0, J 5.4, H-3), 3.32–3.10 (4H, m,
N(CH
3
2
)
3 2
2
2
CH
3
)
2
), 2.18 (1H, dd, J 13.5, J 7.8, H-8a), 2.03 (1H,
2
3
)
2
C
3
2
2
3
dd, J 13.5, J 6.9, H-8b), 1.16 (3H, t, J 7.1, –N(CH
.06–0.95 (9H, m, –N(CH CH ); d (63 MHz,
and 2 × –CH
) 201.8 (dd, JC–F 36.4, 22.2), 155.6, 133.6, 131.2, 120.3,
2
CH
3 2
) ),
1
3
2
1
2
3
)
2
3
C
J
C–F 260.4), 73.0 (d, JC–F 2.5), 66.1 (dd, JC–F 25.4, 20.9), 41.2,
2
CDCl
1
2
3
40.6, 32.3, 22.2, 12.8, 12.3; d (376 MHz, CDCl , 323 K) major
F
3
1
2
2
2
19.2, 115.3 (dd, JC–F 266.8, 256.6), 80.5, 71.7 (dd, JC–F 28.7,
2.6), 44.4, 42.8, 42.2, 38.5, 23.5, 23.4, 14.3, 13.6; d (235 MHz,
conformer: −106.7 (1F, d, JF–F 244.7), −131.3 (1F, dd, JF–F
3
2
F
244.7, JF–H 18.9), minor conformer: −115.1 (1F, d, JF–F 263.0),
2 3
2
2
CDCl
3
) −106.2 (1F, d, JF–F 262.7), −132.4 (1F, dd, JF–F 262.7,
−119.2 (1F, dd, JF–F 263.0, JF–H 17.6); [HRMS (FAB, [M +
3
+
+
J
F–H 22.5); [HRMS (TOF ES ) found: 370.1810. Calc. for
H] ) found: 292.13606. Calc. for C13
H
20NO
4
2
F : 292.13604], m/z
+
+
C
17
H
27NO
4
F
2
Na: 370.1806]; m/z (ES) 348 (100%, [M + H] ).
(ES) 292 (100%, [M + H] ).
2
7 0 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 0 1 – 2 7 1 2